IL-6is a cytokine called B-cell stimulating factor 2 (BSF2) or interferon β2. IL-6 was discovered as a differentiation factor responsible for activation of B-lymphatic cells (Hirano, T. et al., Nature (1986) 324, 73-76). Thereafter, it was found to be a multifunctional cytokine that influences the function of various cells (Akira, S. et al., Adv. in Immunology (1993) 54, 1-78). IL-6 has been reported to induce the maturing of T lymphatic cells (Lotz, M. et al., J. Exp. Med. (1988) 167, 1253-1258).
IL-6 propagates its biological activity through two proteins on the cell. One of them is a ligand-binding protein with a molecular weight of about 80 kD to which IL-6 binds (Taga T. et al., J. Exp. Med. (1987) 166, 967-981; Yamasaki, K. et al., Science (1987) 241, 825-828). IL-6 receptor occurs not only in a membrane-bound form that penetrates and is expressed on the cell membrane but also as a soluble IL-6 receptor consisting mainly of the extracellular region.
The other protein is non-ligand-binding membrane-bound protein gp130 with a molecular weight of about 130 kD that takes part in signal transduction. IL-6 and IL-6 receptor form an IL-6/IL-6 receptor complex, to which gp130 is bound, and thereby the biological activity of IL-6 is propagated into the cell (Taga et al., Cell (1989) 58, 573-581).
IL-6 antagonists are substances that inhibit the transduction of IL-6 biological activities. Up to now, there have been known antibodies to IL-6 (anti-IL-6 antibodies), antibodies to IL-6 receptor (anti-IL-6 receptor antibodies), antibodies to gp130 (anti-gp130 antibodies), reshaped IL-6,IL-6 or IL-6 receptor partial peptides, and the like.
Antibodies to IL-6 receptor have been described in a number of reports (Novick D. et al., Hybridoma (1991) 10, 137-146; Huang, Y. W. et al., Hybridoma (1993) 12, 621-630; international Patent Application WO 95-09873; French Patent Application FR 2694767; and U.S. Pat. No. 5,216,128). A humanized PM-1 antibody was obtained by implanting the complementarity determining region (CDR) of one of them, a mouse antibody PM-1 (Hirata et al., J. Immunology (1989) 143, 2900-2906), into a human antibody (International Patent Application WO 92-19759).
Castleman's disease is a disease first described by Castleman in 1956 as the hypertrophy of lymph nodes in the mediastinum similar to thymoma, in which the lymph nodes display two characteristics: (1) the hypertrophy of lymph follicles, and (2) angiogenesis associated with hyalinization and proliferation of endothelial cells (hyaline vascular type). In addition, it was found that Castleman's disease has another type (plasma cell type) in which many plasma cells are seen in interfollicular stroma. Multicentric Castleman's disease (MCD) is also characterized by the systemic occurrence of lymph nodes having similar histological features. There is no established method of treatment for MCD. Complications or prognostic factors include secondary amyloidosis, interstitial pneumonia, malignant lymphoma, plasmacytoma, Kaposi's sarcoma etc., and thus treatments effective for Castleman's disease are considered also effective for the prevention and treatment of these complications.
On the other hand, angiogenesis is a phenomenon in which new blood vessels are formed during the processes of inflammation, wound healing and cancerous growth, and it is known that vascular endothelial precursor cells in the blood stream, in addition to those formed de novo from the existing blood vessels, contribute to angiogenesis. As diseases in which angiogenesis is involved, there can be mentioned cancer, interstitial pneumonia, rheumatism, Kaposi's sarcoma, psoriasis, diabetic retinitis and the like, and drugs that inhibit angiogenesis are believed to be effective as preventive and/or therapeutic agents for these diseases. The proliferation and migration of vascular endothelial cells are controlled by growth factors such as FGF, HGF, PDGF, TGF-β and VEGF, and cytokines such as IL-1, IL-6,IL-8, TNF, INF-α and IFN-β. It is very difficult to predict how individual cytokines affect angiogenesis since not only does one cytokine has multiple effects but, at the same time, a plurality of cytokines have similar effects.
On the effect of IL-6 on angiogenesis, there are reports that suggest that IL-6 promotes angiogenesis as in a report (Aoki Y. et al., Blood, 93(12):40344, (1999)) that suggests viral IL-6 (vIL-6) stimulates VEGF production in NIH3T3 cells in an in vitro study, and a report (Cohen T. et al., J. Biol. Chem., 271(2):736 (1996)) that suggests IL-6 induces the expression of VEGF, whereas there is a report (Japanese Unexamined Patent Publication (Kokai) No. 4-202139) that indicates that IL-6 inhibits angiogenesis by inhibiting the formation of blood walls by suppressing motility such as the migration of vascular endothelial cells. Furthermore, it has also been reported that the administration of a humanized anti-IL-6 receptor antibody tended to reduce angiogenesis in patients with Castleman's disease (Nishimoto et. al., Blood, 95(1):56-61 (2000)), and in a report (Foss H-D, et al., J. Pathology, 183:44 (1997)) that investigated the expression of VEGF in Castleman's disease and the association of IL-6 and VEGF has been considered a subject that needs further investigation. Thus, much seems to remain to be clarified on the action of IL-6 on angiogenesis in vivo, especially in patients with Castleman's disease.